The subject of the present invention is the use of direct or indirect selective inhibitors of factor Xa which act via antithrombin III, alone and/or in combination with a compound with anti-platelet aggregation activity, for their activity in arterial thromboembolic diseases.
The pharmaceutical compositions containing the combination of antithrombotic and anti-platelet aggregation active ingredients are also included in the invention. The active ingredients constituting the combination are present in the free state or in the form of one of their pharmaceutically acceptable salts.
During the last decade, a lot of attention has been given to studying the role played by platelets in the development of diseases associated with atherosclerosis (myocardial infarction, angina, cerebral vascular accident, arterial diseases of the lower limbs and the like). Moreover, the well-established role of the blood clotting process in arterial thrombosis has allowed the development of numerous medicines which inhibit various clotting enzymes. The discovery of the essential role of thrombin and factor Xa in the thrombotic process has led to the use of anticoagulants being proposed in the prevention and treatment of arterial thrombosis.
Among the anticoagulants available, heparin is the preferred medicine in the prevention and treatment of thromboembolic diseases.
Heparin catalyses, in particular via anti-thrombin III (AT III), the inhibition of two enzymes which are involved in the blood clotting cascade, namely factor Xa and factor IIa (or thrombin). The relative importance of these two activities in the overall activity of heparin remains unknown. Low-molecular-weight heparin (LMWH) preparations contain chains consisting of 4 to 30 monosaccharides which act like heparin on factor Xa and on thrombin but which have the property of being more selective for factor Xa then for thrombin. In spite of this different biological activity profile, low-molecular-weight heparin has an antithrombotic effect as has been demonstrated in studies on animals and on patients suffering from thromboembolic diseases or at risk of forming a thrombus (Hirsch J. et al., J. Thromb. Hemost., 1987, Leuven, Belgium Leuven University Press, 325-348).
Unlike heparin and the LMWHs, some synthetic oligosaccharides, especially those described in EP 84999, have the property of selectively inhibiting factor Xa via antithrombin III but have no activity on thrombin. These synthetic oligosaccharides which correspond to the antithrombin-binding domain (ABD) of heparin are known and manifest an unthrombotic activity in venous thrombosis. These compounds are described in EP 529715 and EP 621282.
The efficacy of these oligonucleotides in the prevention of arterial thrombosis was hardly probable because of their inability to inhibit thrombin.
Indeed, it has long been known in the literature that thrombin plays a key role in arterial thrombosis and this is again confirmed by recent experiments (L. A. Harker, Blood, 1991, 77. 1006-1012). Thrombin inhibitors therefore constitute an effective means of preventing or combating this type of thrombosis.
It has been observed, by comparing the efficacy of heparin to those of direct thrombin inhibitors (direct inhibitor means an inhibitor which inhibits thrombin without requiring AT III), that they are much more effective than heparin for preventing and treating arterial thrombosis (Arteriosclerosis and thrombosis, 1992, 12, 879-885, J. Am. Coll. Cardiol., 1994, 23, 993-1003). The reason for this lack of efficacy is that the heparin/AT III complex cannot, for reasons to do with steric hindrance, inhibit thrombin in a thrombus rich in platelets as is a platelet thrombus.
The low activity of heparin in contrast to direct inhibitors is therefore linked to its need to use AT III. This explanation is further justified by the recent observation that the direct inhibitors of factor Xa which act without AT III are also effective, in animal models of arterial thrombosis (Circulation, 1991, 84, 1741-1748 Thrombosis Haemost., 1995 74, 640-645).
A compound which, on the one hand, acts via AT III and, on the other hand, does not inhibit thrombin, would therefore be expected to possess no activity in arterial thrombosis.